Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency

The use of modified nucleotides to suppress the interferon response and maintain translation of self-amplifying RNA (saRNA), which has been achieved for mRNA, has not yet succeeded. We identify modified nucleotides that, when substituted at 100% in saRNA, confer innate immune evasion and robust long...

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Bibliographic Details
Published in:Nature biotechnology 2024-07
Main Authors: McGee, Joshua E., Kirsch, Jack R., Kenney, Devin, Cerbo, Faith, Chavez, Elizabeth C., Shih, Ting-Yu, Douam, Florian, Wong, Wilson W., Grinstaff, Mark W.
Format: Article
Language:English
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Summary:The use of modified nucleotides to suppress the interferon response and maintain translation of self-amplifying RNA (saRNA), which has been achieved for mRNA, has not yet succeeded. We identify modified nucleotides that, when substituted at 100% in saRNA, confer innate immune evasion and robust long-term protein expression, and when formulated as a vaccine, protect against lethal SARS-CoV-2 challenge in mice. This discovery advances saRNA therapeutics by enabling prolonged protein expression at low doses.The use of modified nucleotides to suppress the interferon response and maintain translation of self-amplifying RNA (saRNA), which has been achieved for mRNA, has not yet succeeded. We identify modified nucleotides that, when substituted at 100% in saRNA, confer innate immune evasion and robust long-term protein expression, and when formulated as a vaccine, protect against lethal SARS-CoV-2 challenge in mice. This discovery advances saRNA therapeutics by enabling prolonged protein expression at low doses.
ISSN:1087-0156
1546-1696
1546-1696
DOI:10.1038/s41587-024-02306-z